Within the past ten years, a new therapeutic regimen, called LAK therapy, has been designed for the treatment of solid tumors. According to LAK therapy, a particular population of the patient's own peripheral blood lymphocytes are activated in vitro with IL-2, hence the name "lymphokine activated killer cells" or "LAK" cells. These LAK cells kill tumor cells, while remaining substantially non-toxic to normal cells [E. Grimm et al, J. Exp. Med., 144:1823 (1982); S. Rosenberg, J. Natl. Can. Inst., 75:595 (1985)]. In the presence of recombinant IL-2 in vivo, LAK cells are capable of inducing the regression of established metastatic tumors in animal models [M. Rosenstein et al, Cancer Res., 44: 1946 (1984); J. J. Mule et al, Science, 255:1487 (1984); R. Lafreniere et al, Cancer Res., 45:3735 (1985); A. Mazumder et al, J. Exp. Med., 159:495 (1984)]. Promising results have, thereafter, been reported in the management of patients with advanced solid tumors, especially renal carcinoma and melanoma, employing an immunotherapeutic approach with LAK cells and recombinant IL-2, or with IL-2 alone [S. A. Rosenberg et al, New Engl. J. Med., 313: 1485 (1985); S. A. Rosenberg et al, New Engl. J. Med., 316:889 (1987); W. H. West et al, New Engl. J. Med., 316:898 (1987)].
Recent investigations on the use of IL-2/LAK cell therapy in leukemic patients indicate that in patients with a limited proportion of detectable residual blasts, this therapeutic approach may result in the disappearance of the leukemic population [D. Gottlieb et al, Brit. J. Cancer, 60:610 (1989)]. However, the same therapy is not successful in patients with advanced disease (90% blasts in the bone marrow) and is associated with significant toxicity as also observed in solid tumor patients [S. Rosenberg et al, New Engl. J. Med., 313: 1485 (1985); S. A. Rosenberg et al, New Engl. J. Med., 316:889 (1987)].
Conventional LAK therapy has several disadvantages. The patient's modified T cells need continuous activation with IL-2 for growth and cytotoxicity. Thus, the process of continuing LAK therapy involves periodic removal and activation in vitro of the patients' normal T cells. Additionally, at the high levels used in LAK therapy, IL-2 is toxic to the patient. The activated T cells are not very cytotoxic and the number of LAK cells that can be produced in vitro and injected in vivo is by necessity limited to a few billion. Few tumors seem to respond to this type of therapy. Thus, while LAK therapy is an improvement over conventional chemotherapy, it is not an optimal therapy for cancer patients.
Analysis of the growth factor requirements and differentiative potential of acute T lymphoblastic leukemias (T-ALL) in children have led to the establishment and characterization of several cell lines bearing the t(8;14) or t(11;14) chromosomal translocations [O'Connor et al, J. Immunol., 145:3779- 3787 (1990); and O'Connor et al, Blood, 77:1534-1545 (1991) (see Table I)]. Cells from more mature T-ALL cases displayed lymphoid commitment regardless of the growth factor in which they were expanded. In contrast, cells from a very immature T-ALL underwent growth factor-dependent phenotypic conversion (lymphoid to myeloid) when cultured in interleukin (IL)-3 and could be reverted to the T-lineage by switching to growth in IL-2 (see, e.g., Table I below). These cells became established as a continuous cell line designated TALL-103/2 [Santoli et al, J. Immunol., 144(12):4703-4711 (1990) and O'Connor et al, J. Immunol., 145:3779-3787 (1990)].
TALL-103/2 cells are IL-2-dependent and produce high levels of IFN-.gamma., TNF-.alpha., IL-8 and GM-CSF upon induction with susceptible tumor cells, IL-2 and monoclonal antibodies (mAbs) specific to CD3 and CD2 antigens. This cell line (CD3.sup.+ TCR.gamma..delta..sup.+) is also endowed with non-MHC-restricted cytotoxic activity against those human tumor cells, including leukemias, which are sensitive to Natural Killer (NK) cells [Santoli et al, J. Immunol., 144(12):4703-4711 (1990)]. The stable expression of cytotoxic function over time in culture renders this cell line useful for studies on the mechanism and regulation of lymphocyte-mediated lysis, both in vitro and in vivo. Although IL-2 is required by the cell line for growth and expression of tumoricidal activity, a number of lymphokines, such as IL-4, IL-6, IL-7, IL-12, and interferon (IFN)-.gamma. synergize with IL-2 in the induction of cytotoxic activity [Santoli et al, J. Immunol., 144(12):4703-4711 (1990)].
There remains a need in the art for therapeutic methods and compositions thereof for cancers which can utilize cytotoxic T cell lines and avoid the present need in conventional LAK therapy for patient's own killer cells, and which can target selected organs (e.g., brain, liver, lung) which are the sites of metastases.